Intended actions, unintended consequences: towards a processual understanding of exercise referral schemes

Whilst the benefits of physical activity have been well documented, many in the UK population remain insufficiently active to substantively benefit their health, placing individuals at greater risk of developing a range of non-communicable diseases and conditions. As a large percentage of the population accesses primary care, at least on an annual basis, the use of this health care sector to advocate increased physical activity has become widespread. Exercise referral schemes (ERSs) have enabled primary care professionals to refer their patients, typically to a local leisure facility, for supervised exercise. ERSs have seen prolific growth across the UK since their conception in the 1990s and yet their effectiveness has remained in question. Despite a variety of research designs being employed, evidence regarding schemes’ effectiveness continues to be inconclusive. Within the existing research literature, the complexity of context within which ERSs operate has remained largely overlooked; specifically, how individual interpretations of ERSs might be co-produced according to the interactions between those central to the service, and how this might influence both service delivery and impact. This study, therefore, aimed to address these lacunae by exploring participants’ understanding of ERSs, and how these perceptions contoured ERS service provision. The research focused on one case-study ERS in the East of England. Semi-structured interviews were employed through a combination of group and one-to-one interviews, with 27 participants (15 patients, 7 exercise practitioners, 5 health professionals) who were central to the ERS at a delivery level, and a further 5 (1 ii district manager, 2 representatives from the County Sports Partnership and 2 representatives from Public Health) one-to-one interviews were conducted with individuals who represented the strategic management of ERSs. A process sociological lens was adopted to provide novel insights into participants’ perceptions of ERSs, their role and their ability to influence ERS service provision. Data were also supported by self-elicited reflections born from the researcher’s ‘insider’ position to the County’s ERS. Thematic analysis generated salient themes that showed conflicting interpretations of ERS service provision, and perceptions of scheme receipt and impact. Data highlighted that the networks of relationships in which individuals were situated not only contoured participant experiences but shaped the delivery processes of ERSs. Individual ‘I’ identities were situated within interdependent networks of ‘we’ and ‘they’ relationships, where identifiable groups were formed according to individuals’ perceived role within the scheme. Relationships between individuals and groups were in a tensile state, marked by power balances that had impacted on service provision but also the associated meaning of ERSs, producing interesting, yet unexpected and unintended outcomes. Such findings could prove useful to policy-makers, those responsible for commissioning ERSs, and practitioners, as well as those in similar roles for other multi-agency interventions. By facilitating enhanced understanding of the complexities of this physical activity intervention, findings suggest how the actions and interpretations of those central to a service can fundamentally alter delivery mechanisms and receipt, potentially influencing the very existence of the intervention, or in this case ERSs

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe (vol 75, pg 2027, 2022)

10.1093/cid/ciac730CLINICAL INFECTIOUS DISEASES75111532-153

Accelerated CREP - RRR: Turri, Buckwalter, & Blouw (2015)

According to the Justified True Belief (JTB) account of knowledge, a person’s ability to know something is defined by having a belief that is both justified and true (i.e., knowledge is justified true belief). However, this account fails to consider the role of luck. In 1963, Gettier argued that JTB is insufficient because it does not account for certain situations, called Gettier cases, wherein a person is justified for believing something true but only because of luck. It is unclear whether lay people’s intuitions about knowledge lead them to agree with Gettier, such that lay people believe that individuals in these cases lack knowledge (referred to as Gettier intuitions). We attempt to provide a robust estimate of the Gettier intuition effect size by replicating Turri and colleagues’ (2015) Experiment 1. The Collaborative Replications and Education Project (CREP) selected this study for replication based on its undergraduate appeal, feasibility, and pedagogical value. However, in light of some inconsistent results, suboptimal designs, and inconsistent evidence for cultural variation (e.g., Machery et al., 2015; Nagel, et al., 2013; Seyedsayamdost et al., 2015; Starman & Friedman, 2012; Weinberg et al., 2001), the improved methodology of Turri et al. (2015) make it an important study to replicate cross-culturally. Therefore, we propose a multisite collaborative preregistered replication of Turri and colleague's (2015) Experiment 1 (35 labs from 14 countries across 4 continents signed up at time of submission; expected minimum N = 1,500). Results of this study are expected to provide a clearer picture of the Gettier intuition effect size, lay people’s theory and practice of knowledge, and potentially cross-cultural similarities and differences. Preprint: [X] Pre-registered protocols: [X

COS Ambassadors

A collection of materials and resources for COS ambassadors